Peroxisome proliferators-activated alpha agonist treatment ameliorates hepatic damage in rats with obstructive jaundice: an experimental study

<p>Abstract</p> <p>Background</p> <p>Peroxisome proliferators-activated receptor alpha (PPARα) activation modulates cholesterol metabolism and suppresses bile acid synthesis. This study aims to evaluate the effect of short-term administration of fenofibrate, a PPARα agonist, on proinflammatory cytokines, apoptosis, and hepatocellular damage in cholestasis.</p> <p>Methods</p> <p>Forty male Wistar rats were randomly divided into four groups: I = sham operated, II = bile duct ligation (BDL), III = BDL + vehicle (gum Arabic), IV = BDL + fenofibrate (100 mg/kg/day). All rats were sacrificed on 7^thday after obtaining blood samples and liver tissue. Total bilirubin, aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP), gamma-glutamyl transferase, (GGT), tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1 β), and total bile acid (TBA) in serum, and liver damage scores; portal inflammation, necrosis, bile duct number, in liver tissue were evaluated. Apoptosis in liver was also assessed by immunohistochemical staining.</p> <p>Results</p> <p>Fenofibrate administration significantly reduced serum total bilirubin, AST, ALT, ALP, and GGT, TNF-α, IL-1 β levels, and TBA (<it>P </it>< 0.01). Hepatic portal inflammation, hepatic necrosis, number of the bile ducts and apoptosis in rats with BDL were more prominent than the sham-operated animals (<it>P </it>< 0.01). PPARα induction improved all histopathologic parameters (<it>P </it>< 0.01), except for the number of the bile duct, which was markedly increased by fenofibrate therapy (<it>P </it>< 0.01).</p> <p>Conclusion</p> <p>Short-term administration of fenofibrate to the BDL rats exerts beneficial effects on hepatocellular damage and apoptosis.</p

Peroxisome proliferator-activated receptor alpha (PPAR alpha) activators induce hepatic farnesyl diphosphate synthase gene expression in rodents

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The GABAergic system: a possible component of estrogenic feedback on gonadotropin secretion in rainbow trout (Oncorhynchus mykiss)

In teleost fish, GTH secretion is controlled by a large number of neuroendocrine factors at the central level and steroid feedback represents an efficient process to synchronize the activity of all the systems involved along the brain-pituitary-gonad axis. Estrogen effects are mediated by specific nuclear receptors that act as transcription factors to regulate the expression of target genes. In order to understand the neuroendocrine mechanisms involved in the estrogen feedback on GTH secretion, we need, as a first step, to know the nature of target cells at the pituitary and central levels. In rainbow trout, some estrogen receptors expressing cells are identified but the nature of a large number of them remains unknown. In this paper, we explain our strategy to identify the central target of estrogen using both in situ hybridization and immunohistochemistry. We focused our attention on GABA neurons of which the distribution, in some central areas, exactly overlaps with that of estrogen receptors expressing cells

Caspase-2, a Novel Lipid Sensor under the Control of Sterol Regulatory Element Binding Protein 2

Caspases play important roles in apoptotic cell death and in some other functions, such as cytokine maturation, inflammation, or differentiation. We show here that the 5′-flanking region of the human CASP-2 gene contains three functional response elements for sterol regulatory element binding proteins (SREBPs), proteins that mediate the transcriptional activation of genes involved in cholesterol, triacylglycerol, and fatty acid synthesis. Exposure of several human cell lines to statins, lipid-lowering drugs that drive SREBP proteolytic activation, induced the CASP-2 gene to an extent similar to that for known targets of SREBP proteins. Adenoviral vector-mediated transfer of active SREBP-2 also induced expression of the CASP-2 gene and the caspase-2 protein and increased the cholesterol and triacylglycerol cellular content. These rises in lipids were strongly impaired following small interfering RNA-mediated silencing of the CASP-2 gene. Taken together, our results identify the human CASP-2 gene as a member of the SREBP-responsive gene battery that senses lipid levels in cells and raise the possibility that caspase-2 participates in the control of cholesterol and triacylglycerol levels

Effects of peroxisome proliferator-activated receptor alpha activation on pathways contributing to cholesterol homeostasis in rat hepatocytes

International audiencePeroxisome proliferator-activated receptor alpha (PPARa) activation by fibrates controls expression of several genes involved in hepatic cholesterol metabolism. Other genes could be indirectly controlled in response to changes in cellular cholesterol availability. To further understand how fibrates may affect cholesterol synthesis, we investigated in parallel the changes in the metabolic pathways contributing to cholesterol homeostasis in liver. Ciprofibrate increased HMG-CoA reductase and FPP synthase mRNA levels in rat hepatocytes, together with cholesterogenesis from [14C] acetate and [3H] mevalonate. The up-regulation observed in fenofibrate- and WY-14,643-treated mice was abolished in PPARa-null mice, showing an essential role of PPAR a. Among the three sterol regulatory element-binding protein (SREBP) mRNA species, only SREBP-1c level was significantly increased. In ciprofibrate-treated hepatocytes, cholesterol efflux was decreased, in parallel with cholesteryl ester storage and bile acids synthesis. As expected, AOX expression was strongly induced, supporting evidence of the peroxisome proliferation. Taken together, these results show that fibrates can cause cholesterol depletion in hepatocytes, possibly in part as a consequence of an important requirement of cholesterol for peroxisome proliferation, and increase cholesterogenesis by a compensatory phenomenon afterwards. Such cholesterogenesis regulation could occur in vivo, in species responsive to the peroxisome proliferative effect of PPARa ligands

ω-3 polyunsaturated fatty acid supplementation for the treatment of heart failure: mechanisms and clinical potential

Heart failure (HF) is a complex clinical syndrome with multiple aetiologies. Current treatment options can slow the progression to HF, but overall the prognosis remains poor. Clinical studies suggest that high dietary intake of the ω-3 polyunsaturated fatty acids (ω-3PUFA) found in fish oils (eicosapentaenoic and docosahexaenoic acids) may lower the incidence of HF, and that supplementation with pharmacological doses prolongs event-free survival in patients with established HF. The mechanisms for these potential benefits are complex and not well defined. It is well established that fish oil supplementation lowers plasma triglyceride levels, and more recent work demonstrates anti-inflammatory effects, including reduced circulating levels of inflammatory cytokines and arachidonic acid-derived eicosanoids, and elevated plasma adiponectin. In animal studies, fish oil favourably alters cardiac mitochondrial function. All of these effects may work to prevent the development and progression of HF. The ω-3PUFA found in plant sources, α-linolenic acid, may also be protective in HF; however, the evidence is not as compelling as for fish oil. This review summarizes the evidence related to use of ω-3PUFA supplementation as a potential treatment for HF and discusses possible mechanisms of action. In general, there is growing evidence that supplementation with ω-3PUFA positively impacts established pathophysiological targets in HF and has potential therapeutic utility for HF patients